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Table 1 Phase 3 clinical trials of NOACs: study design and outcomes

From: A case-based approach to implementing guidelines for stroke prevention in patients with atrial fibrillation: balancing the risks and benefits

Trial name

Trial design

No. of patients

Outcomes (annual rate vs. comparator,a %/y)

Stroke/Systemic embolism

All-cause mortalityb

Major bleedingb

Intracranial hemorrhageb

RE-LYc (dabigatran) [23, 31]

PROBE designd

N = 18113 Dabigatran 150 mg bid: n = 6076

Dabigatran 150 mg: RR 0.66 (95 % CI 0.53, 0.82; p < 0.001 for superiority)

Dabigatran 150 mg: RR 0.88 (95 % CI 0.77, 1.00; p = 0.051)

Major bleeding: Dabigatran 150 mg: RR 0.93 (95 % CI 0.81, 1.07; p = 0.31)

Dabigatran 150 mg: RR 0.40 (95 % CI 0.27, 0.60; p < 0.001)

Dabigatran 110 mg bid: n = 6015

Dabigatran 110 mg: RR 0.91 (95 % CI 0.74, 1.11; p < 0.001 for noninferiority)

Dabigatran 110 mg: RR 0.91 (95 % CI 0.80, 1.03; p = 0.13)

Dabigatran 110 mg: RR 0.80 (95 % CI 0.69, 0.93; p = 0.003)

Dabigatran 110 mg: RR 0.31 (95 % CI 0.20, 0.47; p < 0.001)

Warfarin (adjusted dose, target INR 2.0–3.0): n = 6022

    

ROCKET-AF (rivaroxaban) [25]

Randomized, double-blind, double-dummy, noninferiority trial

N = 14264 Rivaroxaban 20 mg/d: n = 7131

 

HR 0.85 (95 % CI 0.70, 1.02; p = 0.07)

Major and CRNM bleeding: HR 1.03 (95 % CI 0.96, 1.11; p = 0.44)

HR 0.67 (95 % CI 0.47, 0.93; p = 0.02)

Warfarin (adjusted dose, target INR 2.0–3.0): n = 7133

HR 0.88 (95 % CI 0.75, 1.03; p < 0.001 for noninferiority; p = 0.12 for superiority)e

 

Major bleeding: HR 1.04 (95 % CI 0.90, 1.20; p = 0.58)

 

ENGAGE AF-TIMI 48 (edoxaban) [26]

Randomized, double-blind, double-dummy, noninferiority trial

N = 21105 Edoxaban 60 mg once daily: n = 7035

Edoxaban 60 mg: HR 0.79 (97.5 % CI 0.63, 0.99; p < 0.001 for noninferiority; p = 0.08 for superiority)f

Edoxaban 60 mg: HR, 0.92 (95 % CI. 0.83, 1.01; p = 0.08)

Major bleeding: Edoxaban 60 mg: HR 0.80 (95 % CI 0.71, 0.91; p < 0.001)

Edoxaban 60 mg: HR 0.47 (95 % CI 0.34, 0.63; p < 0.001)

Edoxaban 30 mg once daily: n = 7034

Edoxaban 30 mg: HR 1.07 (97.5 % CI 0.87, 1.31; p = 0.005 for noninferiority; p = 0.10 for superiority)f

Edoxaban 30 mg: HR, 0.87 (95 % CI, 0.79, 0.96; p = 0.006)

Edoxaban 30 mg: HR 0.47 (95 % CI 0.41, 0.55; p < 0.001)

Edoxaban 30 mg: HR 0.30 (95 % CI 0.21, 0.43; p < 0.001)

Warfarin (adjusted dose, target INR 2.0–3.0): n = 7036

    

ARISTOTLE (apixaban) [24]

Randomized, double-blind, double-dummy, noninferiority trial

N = 18201 Apixaban 5 mg bid: n = 9120

HR 0.79 (95 % CI 0.66, 0.95; p < 0.001 for noninferiority; p = 0.01 for superiority)

HR 0.89 (95 % CI 0.80, 0.998; p = 0.047)

Major bleeding: HR 0.69 (95 % CI 0.60, 0.80; p < 0.001)

HR, 0.42 (95 % CI, 0.30, 0.58; p < 0.001)

Warfarin (adjusted dose, target INR 2.0–3.0): n = 9081

    

AVERROES (apixaban) [32]

Randomized, double-blind, double-dummy, superiority trialg

N = 5599 Apixaban 5 mg bid: n = 2808

HR 0.45 (95 % CI 0.32, 0.62; p < 0.001)

HR 0.79 (95 % CI 0.62, 1.02; p = 0.07)

Major bleeding: HR 1.13 (95 % CI 0.74, 1.75; p = 0.57)

HR 0.85 (95 % CI 0.38, 1.90; p = 0.69)

Aspirin 81–324 mg/d: n = 279

    
  1. bid twice daily, CI confidence interval, CRNM clinically relevant nonmajor, HR hazard ratio, INR international normalized ratio, ITT intention-to-treat, NOAC novel oral anticoagulant, PROBE prospective, randomized, open, blinded end-point, RR relative risk
  2. aNOACs were compared with warfarin in the RE-LY, ROCKET-AF, ENGAGE AF-TIMI 48 and ARISTOTLE trials and with aspirin in the AVERROES trial
  3. bp values are for superiority
  4. cValues for RE-LY are given as RR
  5. dPROBE design
  6. eITT population
  7. fModified ITT (mITT) population
  8. gThis study was terminated early due to treatment benefit in favor of apixaban
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Thrombosis Journal

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